This invention relates to a stable pharmaceutical formulation, which contains Octreotide as active ingredient for intravenous or intramuscular administration.
As is known, peptides in general, and those that contain a disulphide bridge in particular, present moderate stability in solution. The secondary reactions forming sulphur bridges occur thanks to the presence of free oxygen in the medium. These reactions are favoured by a basic pH. Therefore, to obtain a sufficiently stable formulation the absence of oxygen in the medium and a buffer medium that allows the pH of the solution to be close to 4.0 are required.
From the point of view of compatibility of this system with intravenous administration of the drug, it would be ideal for the pH of the solution to be as near as possible to the physiological pH. This is not possible because, as has been discussed earlier, the formulations at a basic pH do not offer great enough stability. Therefore, for a painless administration of peptides by intravenous route a low strength of the buffer medium in which the active ingredient is dissolved is required so the quantity injected is quickly neutralised by the body of the patient.
From the state of the art, pharmaceutical formulations of peptides that contain acetic acid or lactic acid as vehicle for endogenous administration thereof are already known.
Thus, in the patent ES2010561 (Cavanak, Thomas et al.) a formulation is described that uses a solution of lactic acid and sodium bicarbonate as a vehicle for the intravenous administration of Octreotide.
Furthermore, from the year 1983 to the year 1995, Octreotide was sold dissolved in a solution of acetic acid and sodium acetate as vehicle. However, the formulation that contains acetic acid and sodium acetate presents nociceptive effects and leads to a certain degree of inflammation in the patient.
The nociceptive effect and the production of inflammation are due to the difficulty that the body into which the injection is made has for neutralizing the pH 4.0 solution that is being administered.
The tendency of the current state of the art is to look for administration vehicles which can be neutralized with small quantities of base lacking inflammatory and/or nociceptive effects, and which provide a sufficiently acidic pH, necessary both for aspects relating to production of the product and its storage during its useful life.
The formulation described by Cavanak et al. in the patent above-mentioned follows this tendency as said formulation has a vehicle with lower buffer strength and which, therefore, can be more easily neutralized than the solution with acetic acid and sodium acetate.
A new pharmaceutical formulation has now been discovered for the intravenous or intramuscular administration of Octreotide that contains glycine in addition to the peptide in form of any pharmaceutically acceptable salts thereof and which shows a faster neutralization profile that the existing formulations which contain acetic and lactic acid. Furthermore, injection of the formulation that contains glycine according to the invention is much better tolerated than the formulation with acetic acid and, as with the formulation with lactic acid, lacks nociceptive effects.
Therefore, in accordance with the present invention a novel pharmaceutical formulation is provided which contains Octreotide, or any pharmaceutically acceptable salts thereof, which is characterized in that it contains, as a vehicle for intravenous or intramuscular administration, glycine at concentrations between 10 and 60 mM and because it presents a pH of between 3.0 and 4.2 achieved by means of use of an aqueous solution of hydrochloric acid.
It has been demonstrated that the glycine/HCl formulation of this invention loses buffer strength at pH 3.5 and therefore requires a smaller quantity of base to neutralize it than the formulations with lactic acid/bicarbonate (loss of buffer strength at pH 4.8) and acetic acid/sodium acetate (loss of buffer strength at pH 6.5) belonging to the state of the art.
However, it has been observed that, despite having a lower buffer strength, the formulations with glycine/HCl of this invention offer a high stability between pH 3.0 and 3.6. This fact allows solutions of pH 3.2 to be obtained for intravenous injection in which the Octreotide has a very good stability profile and which is neutralized with small quantites of base.
Furthermore, it has been shown, by means of a study of induction of phlebitis in rabbit ear, using Octreotide as active ingredient, that the effect of injection of the formulation of the present invention dissolved in glycine/HCl in the presence of mannitol as isotonic agent, produces the same effect on the rabbit ears as injection with a control solution of dextrose. The formulation of this invention thus lacks nociceptive and/or inflammatory effects.
As a consequence, the present invention describes the pharmaceutical composition necessary for the application of Octreotide, in form of any pharmaceutically acceptable salts thereof, via intravenous injection. This formulation, which can use different concentrations of glycine and HCl in the range of 10 mM to 60 nM, allows administration, without nociceptive effects or apparent inflammation, of an endovenous injection of Octreotide. This formulation is set to pH values that range from 3.0 to 4.2 and contains an isotonic agent, preferably mannitol or sodium chloride, and optionally an anti-oxidant, preferably phenol.